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Wilkes-Barre, PA, United States

Lecun Y.,Facebook | Lecun Y.,New York University | Bengio Y.,University of Montreal | Hinton G.,Google | Hinton G.,Kings College
Nature | Year: 2015

Deep learning allows computational models that are composed of multiple processing layers to learn representations of data with multiple levels of abstraction. These methods have dramatically improved the state-of-the-art in speech recognition, visual object recognition, object detection and many other domains such as drug discovery and genomics. Deep learning discovers intricate structure in large data sets by using the backpropagation algorithm to indicate how a machine should change its internal parameters that are used to compute the representation in each layer from the representation in the previous layer. Deep convolutional nets have brought about breakthroughs in processing images, video, speech and audio, whereas recurrent nets have shone light on sequential data such as text and speech. © 2015 Macmillan Publishers Limited. All rights reserved. Source


The protocols described here are comprehensive instructions for deriving human embryonic stem (hES) cell lines in xeno-free conditions from cryopreserved embryos. Details are included for propagation, cryopreservation and characterization. Initial derivation is on feeder cells and is followed by adaptation to a feeder-free environment; competent technicians can perform these simplified methods easily. From derivation to cryopreservation of fully characterized initial stocks takes 3-4 months. These protocols served as the basis for standard operating procedures (SOPs), with both operational and technical components, that we set to meet good manufacturing practice (GMP) and UK regulatory body requirements for derivation of clinical-grade cells. As such, these SOPs are currently used in our current GMP compliant facility to derive hES cell lines ab initio, in an animal product-free environment; these lines are suitable for research and potentially for clinical use in cell therapy. So far, we have derived eight clinical-grade lines, which will be freely available to the scientific community after submission/accession to the UK Stem Cell Bank. Source


Claycomb J.M.,Kings College
Current Biology | Year: 2014

Endogenously produced small interfering RNAs (endo-siRNAs, 18-30 nucleotides) play a key role in gene regulatory pathways, guiding Argonaute effector proteins as a part of a functional ribonucleoprotein complex called the RISC (RNA induced silencing complex) to complementarily target nucleic acid. Enabled by the advent of high throughput sequencing, there has been an explosion in the identification of endo-siRNAs in all three kingdoms of life since the discovery of the first microRNA in 1993. Concurrently, our knowledge of the variety of cellular processes in which small RNA pathways related to RNA interference (RNAi) play key regulatory roles has also expanded dramatically. Building on the strong foundation of RNAi established over the past fifteen years, this review uses a historical context to highlight exciting recent developments in endo-siRNA pathways. Specifically, my focus will be on recent insights regarding the Argonaute effectors, their endo-siRNA guides and the functional outputs of these pathways in several model systems that have been longstanding champions of small RNA research. I will also touch on newly discovered roles for bacterial Argonautes, which have been integral in deciphering Argonaute structure and demonstrate key functions of these conserved pathways in genome defense. © 2014 Elsevier Ltd. All rights reserved. Source


MacDougall I.C.,Kings College
American Journal of Kidney Diseases | Year: 2012

Recombinant human erythropoietin (epoetin) has been available for the treatment of renal anemia for more than 20 years, and within the last decade two molecularly engineered analogues darbepoetin alfa and pegylated epoetin beta were introduced as longer-acting erythropoiesis-stimulating agents. Recently, newer strategies for correcting anemia have been explored, some of which remain in the laboratory while others are translating across into clinical trials. Peginesatide has completed phase 3 clinical trials for the treatment of anemia associated with chronic kidney disease; this molecule is immunologically distinct from the erythropoietic proteins, with no cross-reactivity with anti-erythropoietin antibodies. HIF (hypoxia inducible factor) stabilization involves the pharmacologic inhibition of prolyl hydroxylation of HIF-α (the major transcription factor controlling erythropoietin gene expression), thereby preventing its degradation in the proteasome. Hepcidin is the master regulator of iron metabolism, and this peptide is upregulated in inflammatory conditions, including uremia; its antagonism has been shown to cause amelioration of inflammatory anemia in animal models. For the time being, erythropoiesis-stimulating agent therapy remains the mainstay of anemia management in chronic kidney disease, but it is possible that one or more of the strategies discussed in this review may have a future role in the treatment of this condition. © 2012 National Kidney Foundation, Inc. Source


Mekhail K.,Kings College | Moazed D.,Howard Hughes Medical Institute
Nature Reviews Molecular Cell Biology | Year: 2010

Non-random positioning of chromosomal domains relative to each other and to nuclear landmarks is a common feature of eukaryotic genomes. In particular, the distribution of DNA loci relative to the nuclear periphery has been linked to both transcriptional activation and repression. Nuclear pores and other integral membrane protein complexes are key players in the dynamic organization of the genome in the nucleus, and recent advances in our understanding of the molecular networks that organize genomes at the nuclear periphery point to a further role for non-random locus positioning in DNA repair, recombination and stability. © 2010 Macmillan Publishers Limited. All rights reserved. Source

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